clinical epilepsy

1Stephan Eisenschenk, MDDepartment of Neurology

Clinical Epilepsy

www.neurology.ufl.edu/Epilepsy


Seizures vs EpilepsyDefinition: the clinical

manifestation of an abnormal and excessive excitation of a population of cortical neurons

Incidence: approximately 80/100,000 per year

Lifetime prevalence: 9% (1/3 benign febrile convulsions)

Definition: a tendency toward recurrent seizures unprovoked by systemic or neurologic insults

Incidence: approximately 45/100,000 per year Approximately 181,000 people will experience seizures or develop epilepsy each year

Point prevalence: 0.5-1% (2.5 million)14 years or younger

13% 15 to 64 years

63%65 years and older

24%

Cumulative risk of epilepsy through 74 years old: 1.3% - 3.1%

Seizures Epilepsy


Partial (focal) Seizures• Simple Partial Seizure

– no loss of awareness

• Complex Partial Seizure– Impaired consciousness/ level of awareness

(staring)– Clinical manifestations vary with origin & degree

of spread– Presence and nature of aura

• Temporal lobe: smell, epigastric sensation, deja vu

– Automatisms (manual, oral)– Other motor activity

• Frontal: bicycling and fencing posture– Duration (typically 30 seconds to 3 minutes)– Amnesia for event

• Partial Seizure with Secondary Generalization


Localization of Partial Seizure Focus

70%70% 10%10%

20%20%


Temporal Lobe Complex Partial Seizure

Rhythmic 5-7 Hz theta from the mesial temporal lobeRhythmic 5-7 Hz theta from the mesial temporal lobe


Primarily Generalized Seizures• Absence

– Typical (3 Hz spike and wave)– Atypical (2.5 to 4.5 Hz spike and wave, polyspike)– Brief staring (<30sec); automatisms rare; not post-ictal confusion

• Myoclonic– Brief, shock-like muscle contractions

- Head- Upper extremities

– Usually bilaterally symmetrical– Consciousness preserved– Precipitated by awakening or falling asleep– May progress into clonic or tonic-clonic seizure– May be associated with a progressive neurolgic deterioration

– Juvenile Myoclonic Epilepsy (JME)• Polyspike wave

• Onset late adolescence

• Chromosome 6p

– Progressive Myoclonic Epilepsies

• Atonic/ Tonic/ Tonic-Clonic


Absence Seizure

3 Hz spike and wave


Seizure vs EpilepsySeizures

CardiovascularDrug relatedSyncopeMetabolic (glucose, Na, Ca, Mg)Toxic (drugs, poisons)PoisonInfectiousFebrile convulsionsPseudoseizureAlcohol/drug withdrawalSubstance abusePsychiatric disordersSleep disorders (parasomnias, cataplexy)

Nonepileptic Epilepsy(recurrent seizures)

Idiopathic(primary)

Symptomatic(secondary)


Psychogenic Nonepileptic Seizures

• Represent genuine psychiatric disease • 10-45% of refractory epilepsy at

tertiary referral centers• Females > males • Psychiatric mechanism:

dissociation, conversion, unconscious (unlike malingering)

• Association with physical, sexual abuse

• Epileptic and nonepileptic seizures may co-exist

• Video-EEG monitoring often helps clarify the diagnosis

• Once recognized, approximately 50% respond well to specific psychiatric treatment


Epidemiology of Seizures and Epilepsy

0102030405060708090

0 10 20 30 40 50 60 70 80Age

Inci

denc

e pe

r 10

0,00

0

PartialGeneralized tonic-clonicPrimary Generalized

Epilepsy: Incidence Rates by Seizure TypeEpilepsy: Incidence Rates by Seizure Type

Data from Rochester, Minn (1935-1979). Adapted with permission from Annegers JF. In: The Treatment of Epilepsy: Principles and Practice. 2nd ed. Baltimore, Md: Williams & Wilkins; 1997:165-172.

Hauser et al, 1992

Ramsay RE, et al. Neurology. 2004;62(5 suppl 2):S24-S29

Hemorrhage2% Head Trauma

7%

Other*19%

Atherosclerosis15%

Cerebral Infarct

33%

Unknown24%

Head Trauma5%Congenital

4%

Idiopathic85%

Degenerative1%

Neoplastic4%

Vascular1%

Infectious0%

.* Includes known etiologies such as arteriovenous malformation and venous angioma.


Seizure Precipitants

Low (less often high) blood glucose

Low sodium

Low calcium

Low magnesium

Stimulant or other proconvulsant toxicity (i.e., cocaine)

Sedative (i.e., valium or alcohol) withdrawal

Severe sleep deprivation


EEG Abnormalities

•Background abnormalities

-Significant asymmetries and/or degree of slowing inappropriate for clinical state

•Transient abnormalities associated with seizures

-Spikes (< 70 m sec)

-Sharp waves (~70 – 200 msec)

-Spike-wave complexes

•May be focal, lateralized or generalized


EEG Abnormalities


Medical Treatment of First Seizure(s)•Whether to treat first seizure is controversial

•16-62% will recur within 5 years

•Relapse rate for second seizure is reduced by AEDs,

BUT long term prognosis of whether the patient will have refractory epilepsy is not

•Increased risk of relapse

Abnormal imaging

Abnormal EEG

Family history of epilepsy

•Currently, most patients are not treated for the first seizure unless there is an increased risk for relapse


First Tonic-clonic Seizure

0%10%20%30%40%50%60%70%80%90%

100%

0 1 2 3 4

TreatedUntreated

YEARS

0%10%20%30%40%50%60%70%80%90%

100%

0 1 2 3 4

TreatedUntreated

YEARS

Cumulative time-dependent probability of initiating a period of seizure remission according to whether an AED was given after the first tonic-clonic seizure

1 year seizure-free 2 years seizure-free

Treatment Does NOT Improve Prognosis of Epilepsy


Choosing Antiepileptic Drugs• Seizure type/ Epilepsy syndrome• Comorbid conditions• Adverse side effects or events• Interactions/other medical conditions• Pharmacokinetic profile• Cost• Efficacy• ALL FEMALES (and also consider in males):

– Folate 1 - 4 mg/day– MVI– Calcium (1200-1330 mg per day)


First-Generation Branded AgentsDilantin phenytoin 1938 Parke-DavisTegretol carbamazepine 1974 NovartisDepakote divalproex sodium 1978 Abbott

Second-Generation AgentsSecond-Generation Agents

FelbatolFelbatol felbamatefelbamate 19931993 Wallace LaboratoriesWallace LaboratoriesNeurontinNeurontin gabapentingabapentin 19931993 Parke-DavisParke-DavisLamictalLamictal lamotriginelamotrigine 19941994 Glaxo Smith KlineGlaxo Smith KlineTopamaxTopamax topiramatetopiramate 19971997 Ortho-McNeilOrtho-McNeilGabitrilGabitril tiagabinetiagabine 19971997 Abbott LaboratoriesAbbott LaboratoriesTrileptalTrileptal oxcarbazepineoxcarbazepine 20002000 NovartisNovartisZonegranZonegran zonisamidezonisamide 20002000 ElanElanKeppraKeppra levetiracetamlevetiracetam 20002000 UCB PharmaUCB PharmaLyricaLyrica pregabalinpregabalin 20052005 PfizerPfizer

Rational Use of AEDs: Flooding the Market


FDA Indications for AEDs:Monotherapy and/or Add-On Therapy

MonotherapyCarbamazepineDivalproex EREthosuximideOxcarbazepinePhenobarbital

PhenytoinPrimidone

Lamotrigine1

Felbamate1

Topiramate

1Approved for conversion to monotherapy.

Add-On TherapyCarbamazepine LevetiracetamDivalproex ER GabapentinEthosuximide PhenytoinOxcarbazepine TiagabinePhenobarbital Zonisamide

Primidone

Physician’s Desk Reference, 2004.


Treatment of New Onset Epilepsy

Kwan P, Brodie MJ. N Engl J Med 2000; 342: 314-9.

Sz-free w/ 1st AED47%

Sz-free w/ 3rd AED/Polytherapy

4%Sz-free w/ 2nd AED

13%

Refractory/Pharmacoresistant

36%

Sz-free w/ 1st AEDSz-free w/ 2nd AEDSz-free w/ 3rd AED/PolytherapyRefractory/Pharmacoresistant


Kwan and Brodie. NEJM 2000; 342: 314-319.Mohanraj and Brodie. Epil Behav 2005; 6: 382-387


0

10

20

30

40

50 Carbamazepine Depakote DRDepakote ER Depakote sprinklesKeppra LamictalNeurontin PhenytoinTopomax Trileptal

AE

D P

resc

riptio

n V

olum

e (%

)

0-17 18-34 35-44 45-54 55-64 >65 Age Group (yearsAge Group (years))

Why Should Current Prescribing Practices Change?

PharMetrics. April 2002 to June 2003IMS NPA, Dec 2003.Kwan P, Brodie MJ. N Engl J Med 2000; 342: 314-9.

4%13%

47%

36%

Sz-free with 1st AED

Sz-free with 2nd AED

Sz-free with 3rdAED/PolytherapyPharmacoresistant


Rational Use of AEDs: All PrescriptionsMarket Dynamics for All Indications and Epilepsy

TOPAMAX14.8%

TRILEPTAL8.0%

LAMICTAL8.1%

GABITRIL1.8%

ZONEGRAN2.1%

KEPPRA4.7%

NEURONTIN60.6%

0

50000000

100000000

150000000

200000000

250000000

300000000

350000000

400000000

450000000

Second Gen. AEDs First Gen. AEDs

27%

44%

9%

5%

15%

EpilepsyPsychiatric d/ o'sPain disordersHeadache/ migraineOther

0

10

20

30

40


AED

Pre

scrip

tion

Volu

me

(%)

AED

Pre

scrip

tion

Volu

me

(%)

Age Group (years)Age Group (years) PharMetrics. April 2002 to June 2003. Source: IMS NPA, Dec. 2003MAT 03/2004

0-17 18-34 35-44 45-54 55-64 0-17 18-34 35-44 45-54 55-64 >>65 65


“All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.”

Paracelsus (1493-1541)


Summary of Serious and Non-serious Adverse Events of the Newer AEDs

AED Serious Adverse Events Nonserious Adverse Events

Gabapentin None Weight gain, peripheral edema, behavioral changes

Lamotrigine Rash, including Stevens Johnson and toxic epidermal necrolysis (increased risk for children, also more common with concomitant valproate use and reduced with slow titration); hypersensitivity reactions, including risk of hepatic and renal failure, DIC, and arthritis

Tics and insomnia

Levetiracetam None Irritability/behavior change

Oxcarbazepine Hyponatremia (more common in elderly), rash None

Tiagabine Stupor or spike wave stupor Weakness

Topiramate Nephrolithiasis, open angle glaucoma, hypohidrosis (predominantly children)

Metabolic acidosis, weight loss, language dysfunction

Zonisamide Rash, renal calculi, hypohidrosis (predominantly children)

Irritability, photosensitivity, weight loss


Pregnancy and AED Therapy:Risks of Congenital Abnormalities

• Congenital malformations– Most common: orofacial clefts, heart defects– Less common: microcephaly, neural tube defects

• Major malformations– General population: 2% to 4%– Newborns prenatally exposed to AEDs: 4% to 8%– Multiple AEDs and higher doses may substantially increase malformation rate

• Minor malformations– Increased 2 to 3 fold (10% to 30%)

So EL. Med Clin North Am. 1993;77:203-214. Foldvary N. Neurol Clin. 2001;19:409-425.Schachter SC. Epilepsia. 1999;40(suppl 9):S20-S25.Holmes LB, et al. N Engl J Med. 2001;344:1132-1138.


AEDs and Bone Health• Increased incidence of osteopenia, osteomalacia,

and fracture with some AEDs– No prospective trials have been performed to

define the frequency of fractures in epilepsy • Factors associated with reduced BMD

– Polypharmacy– Generalized seizures

• All tested AEDs have been shown to reduce BMD– Primarily associated with enzyme-inducing

AEDs and phenytoin• Strong association for decreasing bone mineral

density– Carbamazepine– Phenobarbital– Phenytoin– Primidone

• Conflicting findings on bone mineral density– Divalproex– Lamotrigine

• Limited information on newer AEDs

0

10

20

30

40


AED

Pre

scrip

tion

Volu

me

(%)

AED

Pre

scrip

tion

Volu

me

(%)

Age Group (years)Age Group (years)

PharMetrics. April 2002 to June 2003. Source: IMS NPA, Dec. 2003Pack AM, et al. Epilepsy Behav. 2003;4:169-174.Ensrud KE, et al. Neurology. 2004;62:2051-2057

0-17 18-34 35-44 45-54 55-64 0-17 18-34 35-44 45-54 55-64 >>65 65


AEDs and Bone Health


Rational Use of AEDsSo Why Should Prescribing Practices Change?

Patients often required long term (or lifetime) treatment due to driving status

State of Florida *15A-5.004 Neurological Guidelines for Applicants with Seizures (*the following changes to the seizure guidelines became effective in August 1992 and have been used as policy since that date)

1. Applicants and licensed drivers should be seizure free for a period of 2 years before being approved for licensing; but if under regular medical supervision, may apply at the end of 6 months for review by the Medical Advisory Board. “Petit mal” or absence seizures and partial seizures with complex symptomology will also follow these guidelines. The isolated seizure with a normal EEG may be reviewed after 3 months.

2. Applicants and licensed drivers who have been approved after 6 months seizure free may be required to submit follow-up reports at the end of 1 year from the date of approval.

3. Applicants and licensed drivers who have a chronic recurring seizure disorder (or who have been treated for such for 1 year) and medications have been discontinued will not be licensed to drive during the period of drug withdrawal and for a period of 3 months following complete cessation of treatment. If the patient has seizures during this period, licensing may be considered after a 3 month seizure free interval upon return to adequate therapy.

4. If there is a question about the seizure type or the medications the applicant of licensed driver is on, it is the prerogative of the Medical Advisory Board to question the treating physician further in an effort to clarify the nature of the seizures.

5. Blood levels below therapeutic levels are to be considered on an individual basis.

6. Applicants and licensed drivers with only chronic nocturnal seizures will be considered on an individual basis.

7. Applicants and licensed drivers with syncopal episodes who have no clear diagnosis established will be considered on an individual basis


Treatment/Evaluation Sequence for Pharmacoresistent Epilepsy

1st Monotherapy AED Trial

2nd Monotherapy AED Trial

Epilepsy Surgery/VNS Therapy/Neuropace Evaluation

Resective Surgery Stimulator Therapy

3rd Monotherapy/Polytherapy AED Trial

Polytherapy AED Trials

4%

13%47%

36%

Sz-free with 1st AED

Sz-free with 2nd AEDSz-free with 3rd AED/Polytherapy

Pharmacoresistant

Kwan P, Brodie MJ. NEJM;342:314-319.

Strongly consider videoEEG Monitoring

Epilepsy

Psychogenic, migraine, syncope, sleep disorders, movement disorder’s, etc.

Non-epileptic


Other Treatments of Epilepsy• Medical

– Experimental AED trials– Ketogenic diet

• Surgical– Resective– Multiple Subpial Transection– Vagal Nerve Stimulator

• Experimental– Thalamic Stimulators– Stereotactic Radiosurgery– Responsive Neurostimulators


Evaluation for Surgery- NeuroimagingMRI

-hippocampal volumetrics

greater than ~0.5cc difference increases chances for seizure remission

-1.5 mm coronal cuts with sequences sensitive to gray-white differentiation and to gliosis

-inversion recovery/high resonance for cortical dysplasia

PET

Ictal/interictal SPECT

MR SpectroscopyDecreased NAA (due to neuronal loss)

Normal to high Cho and Creatine (represents astrocytosis)


Epilepsy Surgery- Neuroimaging

Ganglioglioma DNT

AVM Cavernous AngiomaCortical Dysplasia

Hippocampal atrophy in temporal lobe epilepsy


Evaluation for Surgery- Subdural Grid Electrodes


Left Anterior Temporal Loectomy

clinical epilepsy

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